African American (AfrAm) veterans bear a disproportionate burden of stroke risk as they experience a 1.5-2.5 fold increased risk of stroke compared to Caucasians and an estimated 21% increased risk of dying from stroke. There is a substantial genetic contribution to stroke risk although few stroke susceptibility genes have been identified to date. The overwhelming majority of stroke genetic studies have been conducted in Caucasian populations, with few studies conducted in minority populations such as AfrAms. Objective. The goal of this study is to identify genes that influence the development of ischemic stroke (IS) in AfrAms. We hypothesize that the higher risk of stroke among AfrAms is at least partially attributable to genetic variants of African origin and that environmental factors may modify the effects of genetic variants on the development of stroke. To test this hypothesis, we propose the following aims: 1) conduct an admixture mapping analysis in a large multicenter collection of African American IS cases to identify chromosomal regions associated with stroke risk; 2) perform SNP association and gene-by-smoking interaction analyses using densely-spaced markers to fine map the regions with strongest admixture associations and evaluate if current smoking will modify the genetic effects on ischemic stroke; and 3) follow up putative genes significantly associated with ischemic stroke using targeted sequencing in a subset of samples to discover novel variants that are enriched among cases. To complement these research objectives, the candidate has developed a training program that includes the following elements: 1) further training in contemporary methodologies used in genetic studies; 2) training in stroke epidemiology and pathophysiology; 3) knowledge and skills in bioinformatics; 4) experience in working with multicenter collaborative studies; 5) communication of research results with scientific community. Methods. The project will include 1,215 AfrAm IS cases and 12,000 AfrAm controls, aged 18-89 years old, from four pre-existing studies: Atherosclerosis Risk in Communities Study (ARIC), Genetics of Early Onset Stroke (GEOS) study, the Vitamin Intervention for Stroke Prevention (VISP) and Women Health Initiative (WHI) study. A common set of ~3,000 ancestry informative markers (AIMs) across these studies will be selected to perform case-only admixture mapping among IS cases to identify genomic regions associated with IS in Aim 1. We will then fine map associated genomic regions using densely-spaced markers by first performing study-specific SNP associations in a case-control/case-cohort design and then meta-analyzing study-specific results to pinpoint the genes associated with IS (Aim 2). For Aim 3, we will perform targeted sequencing of 50 cases and 50 controls in a 500~600 kb region for each putative IS- associated gene to identify novel variants that are enriched in stroke cases. All genotyping and statistical analyses will be performed at University of Maryland School of Medicine, Baltimore. Findings. With the large collection of AfrAm stroke cases assembled in this proposal, we are well- powered to identify stroke genes with a relative risk greater than 1.50-fold. The new methods and expertise acquired as a result of this Career Development Award will also equip Dr. Cheng with tools to launch an independent career in genetic epidemiology research within the VA, that will include making future use of DNA biobanking within the recently launched Million Veteran Program. Status. This project is a new submission and there is no update on the project status. Impact. Identifying genes predisposing to stroke in AfrAm could disclose novel stroke mechanisms relevant to both AfrAms and European Americans and ultimately lead to more effective strategies for stroke prevention and treatment in both veterans and the general population. PUBLIC HEALTH RELEVANCE: Ischemic stroke contributes substantially to disability and mortality in African American veterans. The objective of this research project is to identify genes that influence the risk of ischemic stroke in African Americans using a novel statistical approach based on identifying the ancestral origin of alleles at each locus. A deeper understanding of the genetics and pathogenesis of ischemic stroke will facilitate us to develop strategies for stroke prevention, treatment and improving quality of life in US veterans. The objective of the training component is to equip Dr. Cheng with skills to launch an independent research career in studying the health problems of Veterans.